The worldwide spread of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) has created an urgent need for HIV immunogens that can elicit broad protection against infection. Natural HIV infection in man and SIV infection in monkeys often elicit a strong antibody-mediated (B cell) and T cell-mediated immune response. A number of viral antigens targeted by broadly reactive neutralizing antibodies and antigen specific T cells have been identified. The challenge is to develop vaccines with sufficient potency to stimulate an effective immune response to these important viral antigens. Live viral vectors can enhance both T cell and B cell responses by presenting antigens in the most immunogenic way, in the context of an acute infection.
Weak immunogenicity of vaccine antigens is one of the main problems in vaccine development. Several approaches have been tried to improve presentation and enhance immunogenicity of these antigens, including DNA vaccines, non-replicating vectors and live viral vectors (FIG. 8). DNA vaccines have been used to immunize or to prime for immunization. They have the advantage of flexibility and safety, but often lack potency when used alone. By expressing vaccine antigens in the cytoplasm, DNA vaccines may favor endogenous antigen processing and presentation pathways, leading to induction of MHC class I restricted T cells. Similarly, non-replicating viral vectors deliver antigens directly into cytoplasmic pathways needed to elicit a strong T cell response. These vaccine platforms usually require a high immunizing dose, as antigen expression is limited by vector dose. Live viral vectors can immunize at the lowest dose of any vector, sufficient to initiate infection; they immunize as they replicate. Some vectors set up a chronic infection, while others persist for only a few weeks.
Some of the most successful vaccines, such as oral polio virus and measles, mumps, and rubella virus vaccine, consist of live attenuated viruses. These are given at very low doses, so the vaccine strain must grow in the host to produce sufficient viral antigens to elicit an immune response. By simulating a viral infection, they can elicit innate and adaptive immune responses, resulting in antigen-specific T cells and antibody-producing B cells. Through a process of attenuation, the vaccine strains have retained the growth and immunogenicity of wild type virus while losing its pathogenicity and virulence. However, for many pathogenic viruses, such as HIV, SW, RSV and/or hepatitis, it has not been possible to produce a live attenuated vaccine. Thus, additional approaches for creating vaccines for pathogenic viruses are needed.